The overall goal of this Program Project is to generate novel chemical libraries based on potent natural product-derived pharmacophores and to identify promising new lead structures that affect-cancer relevant molecular targets. We intend to exploit recent advances in solid phase and solution phase combinatorial chemistry developed in our laboratories to synthesize unique natural product-based small-molecule libraries. Our synthetic efforts in Project #1 are focused on two highly relevant molecular targets for cancer, namely tubulin, which is the critical target of several clinically active anti-cancer agents, including paclitaxel, vincristine and vinblastine, and dual specificity phosphatase that have been documented to be proto oncogenes and regulators of cell cycle progression. Projects #2 and 3 will be responsible for the in vitro biochemical analyses of compounds generated by Project #1 as well as initial cell proliferation and cell cycle assays. Project #2 will examine the anti-phosphatase activity of newly synthesized library members while Project #3 will evaluate microtubulin disrupting properties in vitro; both Projects will determine the anti-proliferative activity in at least three representative human tumor cell lines. Project #4 will employ high content combinatorial cell biological assays to both validate in vitro assays and further characterize the actions of each compound. Additionally, Project #4 will develop novel temporal-and spatial-sensitive cellular assays suitable for high throughput that may be applicable to a wide variety of cancer-related signal transduction and cell structural targets. With the assistance of the Quantitative Structural Activity Relationship (QSAR)/Bioinformatics Core B, data from each Project will be analyzed to further refine the basic pharmacophore design and substituent content. Preclinical evaluation of the anti-tumor activity or prioritized lead compounds will conducted in Programs #2 and 3 to provide an initial assessment of overall therapeutic potential. The activities of the program Project will be coordinated by the Administrative Core A. Thus, this Program Project combines the power of contemporary chemistry, biology and informatics in an integrated, interdisciplinary manner that is focused on cancer cure.